JPS6136260A - Novel isoindolinyl_alkyl_piperazines and manufacture - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

DETAILED DESCRIPTION OF THE INVENTION The present invention relates to novel isoindolinyl-alkyl-piperazines and pharmaceutically acceptable salts thereof. Other aspects of the invention relate to pharmaceutical compositions and therapeutic methods containing the compound as an active ingredient, which therapy requires a diuretic and an antihypertensive agent.

U.S. Pat. No. 3,198,798 to Zenitz et a'1. and Pandike ('
Van Dyke (U.S. Pat. No. 3,579,524) and British Patent No. 942,866 disclose 3-oxoisoindole compounds in which the N-substituent of the isoindole contains a piperazinylalkylene group. or contains a substituted piperazinylalkylene moiety. Zenitz et al. disclose the use of these compounds to treat injuries to the gastrointestinal tract as well as to control hypertension;
- Kabandijk also describes the use of these compounds as antihypertensive agents. The British patent states that the compound has narcotic, antispasmodic and antitussive properties.

In the treatment of some diseases, it has the effect of suppressing high surface pressure, diuretic effect (especially), and increasing IJ excretion: na
It may be advantageous to use a single drug with ampholytic properties (triuretic). Usually the opposite is true. For example, prazosin, a highly active antihypertensive agent, has antidiuretic effects.

Therefore, active research is being conducted to develop new antihypertensive agents and/or diuretics.

For example, chloroexolone represented by the following structural formula has been reported in the literature as having diuretic and high surface pressure properties.

Regarding this, Cornish et al.
t at,) Noshei, Pharma, Pharmacol,
(J, Pharm.

Pharmacol, ), 18.65-80 (19
66) and Himori et al.
, ) Japan Jay, Pharmacol, (Jpn,
J, Pharmacol, ), 1987.28
(6), 811-818 (Chemi, Abu, [Che
Chem, Abs, [Chem, 8 bsl, 81. 58265
See d). Cornish et al.
, et al.) describe the preparation of phthalimides and ■-oxoisointrins related to diuretic chloroexolone. Himori et al.
tal,) investigated the antihypertensive effect of a combination of chloroexolone and the β-adrenergic system blocker alprenolol in unanesthetized dogs with renal hypertension, and found that blood pressure significantly decreased after the 21st day of treatment. was found to decrease.

Suzuki, et al. reported that antihypertensive diuretics, such as human D-flumethiazide, trianterene, and chloroexolone, have beneficial effects in spontaneously hypertensive rats.

Thus, certain compounds having a 6-chloro-5-sulfamoylisoindolinyl moiety have been reported or evaluated to have digenic and antihypertensive effects, and certain isoindolinyl-alkyl-piperazines 6-chloro-5-sulfamoylisoindolinyl-alkyl-piperazines have not been known until now, although they have been described as having antihypertensive effects.

As used herein, the term "diuretic" refers to high total urine flow and/or high sodium elimination rate.

By the way, 6-halo or trifluoromethyl-2,3-dihydro-3-oxo-5- having a specific substituted alkylpiperazine moiety as the N-substituent of isoindole
It has been found that sulfamoylisoindole compounds have diuretic and/or antihypertensive effects. Preferred compounds according to the invention, such as 6-chloro-2,3
~dihydro-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl]-3-oxo-
1H-isoindole-5-sulfonamide exhibits both diuretic and antihypertensive properties. Some of the compounds of the invention also exhibit in vitro alpha-binding activity and in vivo alpha-blocking activity.

The compound of the present invention has the following structural formula (1).

However, in the general formula (I), It represents an alkyl, lower alkoxy, trifluoromethyl or cyano group, R2 represents a hydrogen atom, a halogen atom, lower alkyl or lower alkoxy, and R3 represents a hydrogen atom or a cyano group.

The compounds of the present invention also include pharmaceutically acceptable salts of the compounds of general formula (I) above.

In a preferred compound, in the above general formula (I), X is halogen, -1 is more preferably chlorine, and n is 2 to
4, Y is substituted phenyl, i.e. (a), where R1 represents hydrogen or halogen, more preferably hydrogen, and R2 represents hydrogen, lower alkyl or lower alkoxy, more preferably methoxy; be.

As used herein, the terms "lower alkyl" and "lower alkoxylo" mean that the carbon chain of each group has 6 carbon atoms.
It is to be understood that this is meant to include straight as well as branched carbon groups, preferably up to 4. Examples are methyl, ethyl, isopropyl, 1-butyl, 1-methylpropyl, 2-methylpropyl, tert-butyl, hexyl, etc. Further, as used herein, the term ``halogenp'' means all members of the halogen group, with chlorine, bromine and fluorine being preferred.

The pharmaceutically acceptable salts of the present invention are characterized in that the anion does not significantly contribute to the toxicity or pharmacological activity of the salt, and as a result, the general formula (1
) and are considered to be pharmacologically equivalent to the bases of (2) and typically include acid addition salts.

In order to form a salt of the substance of the above general formula (I), pharmacologically acceptable acids such as hydrochloric acid, other hydrohalic acids, sulfuric acid, phosphoric acid, nitric acid, fatty acids, alicyclic acids and aromatic acids are used. group acids or heterocyclic carboxylic or sulfonic acids, such as formic acid, acetic acid, propionic acid, succinic acid, glycolic acid, acetic acid, malic acid, citric acid, tartaric acid, ascorbic acid, maleic acid, hydroxymaleic acid or pyruvic acid, fumaric acid acid, benzoic acid, p-aminobenzoic acid, anthranilic acid, p-hydroxybenzoic acid, salicylic acid or p-
Aminosalicylic acid, methanesulfonic acid, ethanesulfonic acid, hydroxyethanesulfonic acid, ethylenesulfonic acid, halogenbenzenesulfonic acid, toluenesulfonic acid,
Mention may be made of naphthalenesulfonic acid or sulfanilic acid.

Known methods can be used for the preparation of these salts. That is, the base of the above general formula (I) and the selected acid are mixed in an inert solvent such as water, ethyl acetate, methanol, dimethylformamide, etc., and the resulting salt is collected by a known concentration method. Alternatively, a method of isolation by crystallization method is used.

The compounds of the present invention are easily produced according to a series of steps as follows.

A Step 1 (TV) Here, n and Y are as defined for general formula (I).

Process 2 Process 3 (Vf) (Vl) O(■) Here, X is as defined above.

Step 4 (■) Reduction Step 1 is a condensation reaction carried out in the presence of a base that reacts with the HBr generated. This reaction is typically carried out at elevated temperatures, for example about 50-200<0>C. Useful solvents are those commonly used in reactions of organic halides with amines. This solvent is preferably acetonitrile and may also be, for example, n-pentanol or dimethylformamide. The base is preferably an alkali metal carbonate, such as sodium or potassium carbonate, or an organic tertiary amine such as N,N-diisopropylethylamine. Other useful bases include, for example, sodium or potassium,
Contains bicarbonates such as bicarbonates or alkali metal hydroxides. This reaction can be carried out in the presence of a catalyst such as potassium iodide.

Step 2 is hydrazine hydrolysis of the phthalimide group,
This can be easily carried out by refluxing the reaction mixture, for example in ethanol.

Step 3 is a condensation reaction, which is carried out, for example, by refluxing the reaction mixture in n-pentanol and removing the ammonia generated.

Step 4 is a reduction reaction in which the 1.3-dioxoisoindole compound (■) is reduced to remove the oxo at the 1-position. The reduction is generally carried out using zinc and acetic acid or tin and concentrated hydrochloric acid in a solvent inert to the reaction at elevated temperatures of 60-150°C for about 6-48 hours. For zinc-acetic acid, 10
Temperatures between 0 and 150°C are preferred, and the reduction is usually carried out in acetic acid at reflux temperature. Furthermore, reduction with zinc-acetic acid is particularly preferred, in which the compound of (I) is made basic, and the known process consists of steps such as extraction and crushing the precipitate of acid addition salts from the extract or crude extract. easily purified. In the case of reduction with tin/a thick hydrochloric acid, 60 to 10
Preferably carried out in methanol at 0°C, formula (I)
The products are more difficult to purify and in some instances form relatively stable complexes with tin salts. Treatment of a compound of formula (I) complexed with tin with hydrogen sulfide under acidic conditions or with tetramethylethylenediamine in an inert solvent such as methanol removes the tin as an insoluble sulfide or tetramethylethylenediamine complex, respectively. and a pure product can be obtained for elemental analysis. However, flame spectroscopy shows that it contains traces of tin.

Compounds of formula (VIII) are formed during the reduction of 1.3-dioxoisoindole compounds of formula (VII) and are considered to form part of the present invention as useful intermediates.

The compound of formula (VIII) can be selectively synthesized and isolated by reducing the compound of formula (VII) in acetic acid at below 100°C, preferably at or near room temperature, with excess zinc. can.

The reduction in step 4 forms part of the unit step of the process according to the invention for the preparation of compounds characterized by the formula below.

where X is hydrogen or trifluoromethyl, n is an integer from 2 to 5, and Y is R2, where R1 is hydrogen, halogen, lower alkyl,
It is a lower alkoxy, trifluoromethyl or cyano group, R2 is hydrogen, halogen, lower alkyl or lower alkoxy, and R3 is hydrogen or a cyano group.

This method is based on (a) 1゜3 shown by the following general formula (■).
~Step of reducing a dioxoisoindole compound or a 1-hydroxy-3-oxoisoindole compound represented by the general formula (■): 0 (■) I-1 where XSn and Y are as defined above, or (b) a 4-aminopiperidine compound of formula (V): where n and Y are as above and the following formula (■): where X is as above and R5 is an amino group , a halogen atom, a lower alkoxy group, R1 represents a carbamoyl group or a formyl group as a halogen atom or R, CH2- group, and R5 and R1 together can also represent an oxygen atom. in an inert solvent, or (C) formula (X): where n and
is as described above, is reacted with a compound of formula (XI): Z-Y (XI) where Y is as described above and Z is a reactive leaving group. Step;

The sulfamoyl intermediate of the above formula (■) should be understood to include, in particular, compounds such as, preferably, X is a halogen atom or trifluoromethyl, R5 is a lower alkoxy group, especially a methoxy group, Compounds in which R4 is halogen are preferred.

Known methods, such as those exemplified in European Patent Application No. 26.7.49, are utilized for the preparation of intermediates of formula (]X) and (X).

Looking at the reaction between the piperazinyl compound of formula (X) and the compound of formula (X I), n-pentanol tf is reacted with an inert organic solvent such as dimethylformamide at a high temperature of about 50 to 200°C. basic condensing agents, preferably alkali metal hydroxides, carbonates or bicarbonates, such as carbonate, potassium carbonate, sodium bicarbonate or potassium bicarbonate or organic tertiary amine bases, such as triethylamine or pyridine. It is carried out in the presence of etc. Intermediates of formula (X) are obtained by catalytic debenzylation of compounds of formula (I) in which the group Y is benzyl. Compounds of formula (XI) are available commercially or prepared as described herein.

The term "reactive leaving group" as used for "Z" in formula (XI) means a reactive esterified hydroxy group, e.g. inorganic or organic acids or e.g. benzenesulfonic acid,
It is obtained when esterified with an organic sulfonic acid such as p-bromobenzenesulfonic acid or p-toluenesulfonic acid. Particularly preferred leaving groups are chlorine or bromine.

The compounds of formula (I) have antihypertensive and/or diuretic properties, which can be demonstrated by standard pharmacological models known to correlate with the effects in humans. For use in suppressing hypertension, the above-mentioned known models include temporarily hypertensive rats and DOCA-salt hypertensive rats.

Spontaneous hypertensive rats, body weight 300-400, previously conditioned for this treatment.
G male rats are prewarmed in a heating chamber (30° C.) for 10-20 minutes and then confined in a wire mesh container at this temperature. Cardiac systolic blood pressure and heart rate were measured using the tail cuff method using a pneumatic pulse transducer and a biotachometer.
0.25% Methocel (aqueous solution) or 5rr+j! The test compound suspended in the vehicle in a unit dose with a volume equal to /kg was measured before oral administration and at 2.4 and 24 hours after administration. Blood pressure and heart rate are recorded as changes from hourly measurements on vehicle-treated controls, taken periodically to ensure that vehicle has no effect.

DOCA-Salt Hypertensive Rats Initially, male rats weighing 80-100 g were surgically implanted with two 50 mg deoxycorticosterone acetate (DOCA) pellets subcutaneously in the abdomen of each rat, and optionally treated with 1% physiological saline. The patient was given high blood pressure. After 3 weeks, change the 1% saline to distilled water. Part 1
After a week, animals are anesthetized with methoxyflurane and mean arterial blood pressure (MABP) and heart rate are recorded by a catheter inserted into the artery via the left common corotid artery. A heparin-filled catheter is passed under the skin and protrudes behind the head. After 2 days, MABP and heart rate were measured with vehicle (Q, 0.9 of 25% methocel).
% physiological saline solution) or suspended in vehicle in a unit dose of volume equal to 5 mg/kg were measured before oral administration and 4 hours after administration.

Regarding diuretic uses, Lipschitz et al.
itz, et al,) J, Pharmacol.

Ixp, Sepra, (Pharmacol, Bxp,
Mention may be made of the diuretic screen method for unanesthetized rats described in J. Therap, ), 79-97 (1943).

In this test, the administration responses of diuretic, IJum excretion increasing, and potassium excretion increasing properties are measured by oral administration of the test substance.

As mentioned above, preferred compounds of the invention that have both diuretic and antihypertensive properties are 6-chloro-2,3-dihydro-2-[3-[3-(2-methoxyphenyl)-1]
-piperazinyl]-propyl]-3-oxo-1H-isoindole-5-sulfonamide (hereinafter MJ15 (1
3) 7).

It exhibits a dose-dependent natriuretic response at doses ranging from 3.0 to 30 mg/kg body weight.

As an antihypertensive agent, MJ15(13)7 is demonstrated to be active in DOC8-hypertensive rats and spontaneously hypertensive caries. In the latter, M.J.
15(13)7 shows a dose-dependent reduction in cardiac systolic blood pressure at doses of 3.0-30 mg/kg body weight, with an antihypertensive effect observed in about 2 hours. MJ15
(13) 7 also has binding activity for both C1 and α2 sites.

- As mentioned above, the compound of formula (T) has diuretic and/or anti-hypertension properties, and preferably has diuretic and anti-hypertensive properties in an auxiliary manner. Accordingly, another aspect of the present invention is directed to a method of treating hypertension, which method comprises administering to a mammal a compound of formula (I) or a pharmacologically acceptable acid salt thereof, which is effective in controlling hypertension. The treatment consists of systematic administration in such amounts as needed for such treatment. Preferred compounds are those represented by formula (I) in Example 1.
2.3.4.5.9.10.11 and 12 products. Most preferred is 6-dihydro-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl]-3-oxo-I H-isoindole-5 - is a sulfonamide. The term systematic administration includes oral and parenteral routes of administration, but
Oral administration is preferred. Examples of parenteral administration are intramuscular, intravenous, intraperitoneal, rectal and subcutaneous administration. Dosage will vary depending on the mode of administration and also on the type of compound chosen. Generally speaking, about 0.1 to 5 per kg of body weight of mammals.
It is sufficient to administer 0 mg of a compound of formula (1) in a single or multiple dose regimen. According to conventional clinical practice, compounds of formula (I) are administered at doses significantly lower than the amount of the compound considered to be effective. If, after appropriate trials, antihypertensive and/or diuretic responsiveness is insufficient, the dose is increased in small increments until optimal effect is reached.

When administered as an antihypertensive agent in general clinical practice, the compound of formula (1) is administered at doses of 3 to 300 mg/day.
It is administered orally in the same manner as pyrazosine in doses of n+g, preferably 7 to 280 mg. Doses suitable for parenteral administration are generally relatively small, usually 1/2 to 1/2 of the dose suggested for oral administration.

When carrying out antihypertensive and/or diuretic therapy, the active ingredient of formula M) and its pharmacologically acceptable acid addition salts are preferably administered together with a pharmaceutically acceptable carrier; forms part of the present invention. Dosage forms suitable for oral administration are tablets, dispersible powders, granules, capsules, syrups and elixirs. Examples of dosage forms for parenteral administration are solutions, suspensions, dispersions, emulsions, and the like. The composition for oral administration is 1 or 2 or more.
- may contain known adjuvants such as sweetening agents, flavoring agents, coloring agents and preservatives to give a pharmaceutically elegant composition. In addition to the active ingredient, the tablets contain pharmaceutically acceptable excipients, inert diluents such as calcium carbonate, carbonate, lactose and talc;
Granulation and disintegrants such as starch and alginic acid;
Binders such as starch, gelatin and acacia; and lubricants such as magnesium stearate, stearic acid and talc may be included. The tablets may or may not be coated by known methods to delay disintegration and absorption in the gastrointestinal tract.

This coating provides a long-lasting effect. Similarly, suspensions, syrups and elixirs can contain, together with the active ingredient, the known auxiliaries used for preparing such compositions, such as suspending agents (methylcellulose, gum tragacanth and alginic acid). (sodium), wetting agents (lecithin, polyoxyethylene stearate), and preservatives such as ethyl p-hydroxybenzoate. Capsules may contain the active ingredient alone or with inert diluents such as calcium carbonate, calcium phosphate and carrion. Injectable compositions are formulated as known in the art and may contain suitable dispersing or wetting agents and suspending agents similar or equivalent to those set forth above.

The following examples illustrate the invention.

All temperatures are in degrees Celsius, and Thom
Melting points determined with a capillary apparatus (as Hoover) are uncorrected.

Example 1:6. -chloro-2,3-dihydro-2-[3
~[,4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3 ~oxo1H-isoindole-5-sulfonamide 0 0 [H3 This compound is prepared according to the following steps.

Step (a): Synthesis of N-[3-[3-(2-methoxyphenyl)-1-piperazinyl]propyl]-7talimide ■-(0-methoxyphenyl)piperazine (0.19 mol), N-( 3~bromopropyl)phthalimide (0,
186 mol) and finely ground potassium carbonate (0,465 mol) in 375 mj of a7tonitrile
The mixture was heated under reflux for 6 hours. The cooled mixture was evaporated under reduced pressure and the residue was diluted with water (800 mj) and chloroform (4 mj).
Extraction was carried out at ×350 mm. After drying (MgSO,), the combined extracts were evaporated under reduced pressure. Remove the residue under high vacuum (
<Q, 05mmHg) at room temperature for 16 hours to form a yellow solid. 2. Qg (yield ~100%) was obtained. m,
p, −85 to 93° C., spectral data were consistent with the title structure.

Step (b): 1-(3-amino-1-propyl)-4-
Synthesis of (2-methoxyphenyl)piperazine The compound produced in step (a) above (0,184 mol),
A mixture of hydrazine hydrate (0,184 mol) and ethanol (750 mj) was heated to reflux for 16 h. The cooled suspension was filtered and the filtrate was made basic (pH 10) with 10% sodium hydroxide solution and a white The suspension was dissolved. Volatiles were removed under reduced pressure and the residue was diluted with water (400 ml). The product was dissolved in chloroform (5 x 400 ml).
Extracted by i. After drying (MgSO,) the combined extracts were evaporated under vacuum and the resulting orange oil was evaporated under high vacuum (
Maintained at <0.05mmt1g> for 16 hours, 43.6
g (95% yield) of an orange oil was obtained. The spectral data were consistent with the above structure. This material was used in the following procedure without further purification.

Step (C) + 6-chloro-2-[3-[4-(2-
methoxyphenyl)-1-piperazinyl]propyl]-
Synthesis of 2,3-dihydro-1,3-dioxo-L H-isoindole-5-sulfonamide 4-chloro-5-sulfamoylphthalimide (0,0
76 mol), the compound obtained in step (b) above (0,076 mol)
mol) and n-pentanol (375 mA) was heated to reflux for 16 hours. A gas inlet tube was installed just above the solvent surface to introduce refluxing raw dry nitrogen to facilitate the removal of generated ammonia. Upon cooling, a solid precipitate forms;
This was collected by filtration. Crushing with diethyl ether gave 22.8 g of a yellow solid (61% yield). m,
T)+ -121-137°C, spectral data consistent with the title structure. It was also shown that it contained a slight (2%) n-pentanol impurity. This material was used in the following step without further purification.

Further pentanol-ether treatment gave the sample a pale yellow m, p, 134-137°C material.

Elemental analysis: c22+25c*N, o5s - Theoretical value as N20: C51,71; N5.33; N10.9
6; H2O3,53 Actual value: C51,71; N5.36; N10.72
.

H2O3,09 Step (d) Production of the title compound The compound obtained in the above step (C) (0, (14) 5 mol),
fine zinc powder (0.25 mol) and glacial acetic acid (500 ml)
) mixture was stirred at room temperature for 1 hour. The suspension was then heated to reflux for 4 hours. The cooled mixture was filtered to remove excess zinc and zinc salts. The filter cake was soaked in acetic acid (50m
The combined filtrates were evaporated under vacuum to give an orange oil. Saturated bicarbonate) IJum aqueous solution (2
,50m R) and ethyl acetate (,300ml) were added to the residual oil. The layers were separated and the aqueous phase was extracted with ethyl acetate (5 x 300rr + 4ml).The extracts were combined and 1
．． Dry (MgSOl) and evaporate in vacuo. The residue was dissolved in warm ethyl acetate (50mj7) and 8.9N
Upon treatment with ethanolic hydrogen chloride (10 ml) a beige solid precipitate forms immediately. The cooled suspension was filtered and the cake was ground up under vacuum (<0.05O5m
17.8 g (77% yield) of analytically pure 6-chloro-2-[3-[3
-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide was obtained as the hydrochloride (MJ 15(13)7-1). m, p, -158-170°C (decomposed). Beige solid. This compound is diuretic, antihypertensive and alpha
- Has use as a binder.

Elemental analysis: C22H27CI! Theoretical value as N, O, 5-HCl: C51,26; N5.48; N], 0.87
; Actual value: C51,11; N5.61'; N10.9
ONMR (DMSO-d6): 2.18 (2, m)
; 3.15 (6, m); 3.53 (6, m); 3.7?
(3, s); 4.62 (2, s); 6.94 (4, m)
7.78 (2, bs); 7.95 (L s); 8.
20 (1, s); 11. '43 (1, bs) I
R (KBr) Near 55.1o2o1117o1124
0.1330.1450.1'500°1615.16
75 (cm-') The hydrochloride salt of the title product prepared as above was suspended in isopropanol (12 mjl!/g>), heated on a steam bath for 0.5 h, filtered while hot, The product was dried in a vacuum oven at 80°C to give analytically pure 6-chloro-2,3-dihydro-
2-[3-[3-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide was dissolved in 374 mol hydrochloride (MJ1
5(13), '1-IA). m', ,p,
-270 to 272°C (decomposition).

Elemental analysis: C22H2, ClN40. s・3/4H,C
j! Theoretical value: C52,'19;N5.52; N11.0
6.

C112,25 Actual value: C52,'36;N5.66; N11.0
2; Cj! 11.9O NMR'(DMSO-d6)': 2.20 (2,
m); 3.1'5 (6, m); 3.5'0 (6, m);
3 near 9 (3, s); 4.65 (2, s); 6.95 (
4, m); 7.80 ('2, bs); 7.96 (1, s
); 8.22 (1, s); 11.50 (1, bs') I
R (KBr) Near 50.1020.1170.12
45.1335.1450.1500.1615.16
85 A sample of the title product, prepared as the hydrochloride salt, was crushed with hot isopropanol and then dried under vacuum at about 100°C for 72 hours to give 6-chloro-2°3-dihydro-2”
-[3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide monohydrochloride as a 2-propatol solvate (hereinafter referred to as MJ15 (13 )7-1-3) was obtained. It has m, p, 278-27'9°C (decomposed), and the following elemental analysis and NMR values.

Elemental analysis: C22H27CβN, o, S-HC, 1!・
Theoretical value as 0.2C3H60/0.15H20: C5
1,20; N5.68; N10.57; H2O0,
5L actual value: C51,52;, N5.75; N10.51;
H2O0,7? NMR (DMSO-ds): 2.17 (2, m
); 3.12 (6, m); 3.44 (6, m); 3.7
6 (3, s); 4.63 (2, s); 6. (22)('
I, m); 7.75 (2, b s ); 7.94
(1, s); 8.20 (1, 5) IR (KBr) near 50.1245.1165.1
330.1500.1615.1670 Example 2: 6-
Chloro2-[3-[4-(3-chlorophenyl)-
1-piperazinyltopropyl]-2,3-dihydro-
3 -Oxo-1H-isoindole-5-sulfonamide hydrochloride/'AH20 0Cβ The above compound was obtained as a hydrochloride/dihydrate according to the following steps.

Step (a): Synthesis of N-[3-[4-(3-chlorophenyl)-1-piperazinyl]-propyl]phthalimide 1-(m-chlorophenyl)-piperazine (0,025
mole), N-(3-bromopropyl)-phthalimide (
0,025 mol), N,N-diisopropylethylamine (0,025 mol), potassium iodide (0,0(13
) mol) and acetonitrile (20 mj) was heated under reflux for 16 hours.

The cooled mixture was evaporated under vacuum. Water (100ml
) was added to the dark residue and the product was dissolved in chloroform (4xl
25mj? ) was extracted. Combine the extract with water (100 m
11), dried over Mg5O and evaporated under vacuum to give 10.7 g of an orange oil which solidified on standing. Crush this with dry ethanol and
0.2 g of white solid (98% yield) was obtained. Spectral data were consistent with those above.

Step (b): 1-(3-amino-1-propyl)-4-
Synthesis of (3-chlorophenyl)piperazine This structure was carried out analogously to step (b) of Example 1.

However, 0.02 mol of the product of step (a) of this example is used in place of the product of step (a) of Example 1, and the hydrazine is the same as that used in step (b) of Example 1. used in such amounts as to give the molar ratio. The reaction gave 5.1 g of clear oil (80% yield). The spectral data were consistent with the above structure. This material was used in the following steps without further purification.

Step (C): 6-chloro-2-[3-[4-(3-
chlorophenyl)-1-piperazinyl]propyl]-2
Synthesis of ,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide This step was carried out according to the method and molar ratio of step (C) of Example 1, and was carried out using the method and molar ratio of step (b) of this example. 0.019 mol of product was used in place of the product of Example 1, step (b).

This reaction gave a waxy solid. This material was collected and crushed with acetonate IJ to give 5.95 g of a yellow solid (
Yield: 62%). m,p,1(22)-195℃
(Disassembly). The spectral data were consistent with the above structure. This material was used in the next step without further purification.

Step (d) Synthesis of the title compound This step was carried out according to the method and molar ratio of step (d) of Example 1, with 0.012 mol of the product of step (C) of this example being added to step (C) of Example 1. was used in place of the product. This reaction yielded 5.2 g of foamy residue. This material was dissolved in hot ethyl acetate (150 mA) and treated with 9N ethanolic hydrogen chloride (3.5 mA), and the mixture was cooled to room temperature. The filtered fixate was crushed with acetonitrile, collected by filtration, and 16 hours at °C under vacuum (<0.05
mmHg ) and 5.0 g (79% yield) of analytically pure 6-chloro-2-[3-[l-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3
~dihydro-3~oxo-1H-isoindole-5-
Sulfonamide hydrochloride was obtained as Z hydrate.

m, p, -1/10-175°C (decomposed); white solid.

Elemental analysis: C2, N2. Cl2N, (13)S-HCI
・0.5) Theoretical value as 120: [37,69; H4,96; N10.5.9
.

H2O1,70 Actual value: [37,99; N5. (13) :N10.6
5.

H2O1,64 The spectral data were consistent with the title structure.

Example 3: 6-chloro-2,3-dihydro-2-[2-
[1-(2-methoxyphenyl)-1-piperazinyl]
Ethyl]-3-oxo-1H-isoindole-5-sulfonamide 5 This compound was prepared according to the following steps.

Step (a): Synthesis of N-[2-[4-(2-methoxyphenyl)-1-piperazinyl]-ethyl]-7talimide This step was carried out by the method and molar ratio of step (a) of Example 1. Ta. However, 0.026 mol of N-(2-methoxyphenyl)piperazine was used, and N-(2-methoxyphenyl) was used instead of N-(3-bromopropyl)phthalimide.
Piperazine was used. This reaction yielded 4.25 g of a white solid (45% yield). m,p,=76-81℃
, the spectral data matched the structure shown. This material was used in the following steps without further purification.

Step (b): 1-(2-amino-1-ethyl)-4-(
Synthesis of 2-methoxyphenyl)-piperazine This step is carried out in the manner and molar ratio of step (b) of Example 1, with the exception that the reaction product of step (a) of this example is 0.0
12 mol were used in place of the reaction product of step (a) of Example 1. The reaction yielded 2.12 g of a clear oil (75% yield). The spectral data were consistent with the above structure. This material was used below without further purification.

Step (C): 6-chloro-2-[2-[4-(2-
methoxyphenyl)-1-piperazinyl]ethyl]-2
Synthesis of ,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide This step was carried out in the manner and molar ratios of step (C) of Example 1, with the exception of step (b) of this example. Biomorphs of 0. ．． 009
mol was used instead of the product of step (b) of Example 1. This reaction gave a brown precipitate. This material was triturated with hexane-dioxane (3:1) to give 3.25 g of a light brown precipitate (80% yield). m, p.

-198-214℃. The spectral data were consistent with the displayed structure. This material was used below without further purification.

Step (d): Preparation of the title compound This step was carried out in the manner and molar ratios of step (d) of Example 1, except that 0.007 mol of the product of step (C) of this example was added to the method of step (d) of Example 1. It was used in place of the product in (C). The reaction gave a yellow oil. This material was diluted with ethyl acetate (10 ml) and allowed to crystallize. A pale yellow solid was collected and stored under vacuum (<0.05 mm f1) at room temperature for 72 hours.
g) and 0.97 g (32% yield) of analytically pure 6-chloro-2,3-dihydro-2-[i[4-
(2-methoxyphenyl)-1-piperazinyl]ethyl]-3-oxo-1H-isoindole-5-sulfonamide was obtained. m, I), 212-215°C (decomposition);
Pale yellow solid.

Elemental analysis: C2, N2. , CI N, O, S: Theoretical values: C54,25; N5.42; N12.05.

Actual value: C54.25; N5.37; N11. (22
) The spectral data were consistent with the title structure.

Example 4: 6-chloro-2,3-dihydro-2-(:3
~[3-(2-methylphenyl)-1-piperazinyl]propyl]-3 ~oxo-1H-isoindole-5-sulfonamide This compound was synthesized according to the following steps.

Step (a): N-[3-[3-(2-methylphenyl)
Synthesis of 1-piperazinyl]-propyl]phthalimide This step was carried out using the method and molar ratios of step (a) of Example 2, except that N-(2-methylphenyl)-piperazine (0,028 mol) was replaced with 1- (m-chlorophenyl)-piperazine was used instead. This reaction results in 11.1
g of an orange oil was obtained. The spectral data were consistent with the above structure. This material was used below without further purification.

The starting material N-(2-methylphenyl)-piperazine was prepared from the corresponding dihydrochloride by converting the salt into sodium metal (0,0
87 mol) in methanol (150 ml) at room temperature. The resulting mixture was stirred at room temperature for 4 hours.

The precipitated sodium chloride was filtered off. The filtrate was evaporated under vacuum and the residue was crushed with acetonate (50 ml). The mixture was filtered and the filtrate was evaporated under vacuum to give 7.15 g of a yellow oil (yield ~100%). The spectral data were consistent with the free base. This material was used without further purification.

Step (b): 1-(3-amino-1-propyl)-4-
Synthesis of (2-methylphenyl)piperazine This reaction was carried out in the manner and molar ratios of step (b) of Example 1, except that the product of step (a) of this example (0,028 mol) was used in step (b) of Example 1. It was used in place of the product in (a).

The reaction gave 6.5 g of an orange oil (98.5% yield). The spectral data were consistent with the title structure. This material was used below without further purification.

Step (C) + 6-chloro-2-[:3-[4-
Synthesis of (2-methylphenyl)-1-piperazinyl]propyl)-12,3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide This step is carried out by the method of step (C) of Example 1. and the molar ratio of the product of step (b) of this example (0.02 mol)
was used in place of the product of step (b) of Example 1.

This reaction gave a yellow solid. This material was triturated with ether to give 4.3 g (45% yield) of a yellow solid. m, p, -133 to 145°C (decomposition). The spectral data were consistent with the title structure. This material was used without further purification.

Step (d): Preparation of the title compound This step was carried out using the method and molar ratios of Example 10, step (d). However, the product of step (C) of this example (0,009
mol) was used instead of the product of step (C) of Example 1. The reaction gave 3.5 g of a beige waxy solid. This was crushed with isopropanol (50 m, 1 tube), the suspension was filtered, and the precipitate was stored at 50°C for 16 hours in a vacuum (
40-50 mmHg) to give 2.2 g (yield: 5
0%) of analytically pure 6-chloro-2,3-dihydro-2[3-[4-'' (2-methylphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole- 5-sulfonamide was obtained. m, p, = 19
3-198°C (decomposed); beige solid.

Elemental analysis: C22H2, Cl1N, (13) S Theoretical value: C57,07; H5,88; N12.10; Actual value: C57,30; H6,00; N11.85 Spectral data were consistent with the title structure.

Example 5: 6-chloro-2,3-dihydro-3-oxo-2-(3-[4-(phenylmethyl)-1-piperazinyl]propyl]-1H-isoindole-5-sulfonamide This compound is It was synthesized according to the following steps.

Step (a); N-[3-[4-(phenylmethyl)-
Synthesis of 1-piperazinyl]-propyl]-7talimide This reaction was carried out using the method and molar ratios of step (a) of Example H. However, 1-benzylpiperazine (0,028 mol) was used instead of 1-(m-chlorophenyl)-piperazine. The reaction yielded 10.5 g of an orange oil (100% yield).

The spectral data were consistent with the structure described in 1. This material was used in subsequent steps without further purification.

Step (b): 1-(3~amivar 1-propyl)-4=
Synthesis of (phenylmethyl)piperazine This reaction was carried out in the manner and molar ratios described in step (b) of Example 1. Note that the product of step (a) of this example (0,028 mol) was used in place of the product of step (a) of Example 1. This reaction yielded 6.1 g of a clear oil (yield (22)%). The spectral data were consistent with the above structure. This material is described below without further purification.

Step (C): 6-chloro-2-[3-[4-(phenylmethyl)-1-piperazinyl]propyl)-2,
Preparation of 3-dihydro-1,3-dioxo-1H-isoindole-5-sulfonamide This reaction was carried out in the manner and molar ratios of step (C) of Example 1. However, the product of step (b) of this example (0,021
mol) was used instead of the product of step (b) of Example 1. This reaction produced 7.7 g of yellow solid (yield 77%).
) was obtained. The melting point of this product was 180-183°C. A portion of this material (1.6 g) was crushed with methanol to yield 1.3 g of a yellow solid with m, p, 180-183°C (decomposed).

Elemental analysis: C22H25 (J!N, theoretical value as 0.S: C55.40, N5.28; N11.75 actual value:
C55,73, N5.55; N11.48 spectral data were consistent with the structure described above.

Step (d): Preparation of the title compound This reaction was carried out as described in step (d) of Example 1 and under the molar numbers. However, the product of step (C) of this example (
0.013 mol) was used instead of the product of step (C) of Example 1. The reaction gave a white solid, which was triturated with ethyl acetate-ether (1:1) and the suspension was filtered. Sedimentation was carried out at 80 tons for 16 hours under vacuum (<0.05 m
mHg) to give 4.3 g (74% yield) of analytically pure 6-chloro-2,3-dihydro-3-oxo-2-[3-[4-(phenylmethyl)- 1-Piperazinyl]propyl]-1H-isoindole-5-sulfonamide was obtained. m, p, -187-191℃ (decomposition)
;White solid.

Elemental analysis: C22H27Cj! Theoretical values for N and (13)S: C57,07: N5.88; N12.10 Actual values: C57,16; N5.52; N12.07 The spectral data were consistent with the specified structure.

Example 4: 6-chloro-2-[3-[4-(3-diatu-2-pyridinyl)-1-piperazinyl]propyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfone Amide This compound was prepared as a hydrated hydrochloride salt according to the following steps.

Step (a): Preparation of I-(3-cyano-2-pyridinyl)piperazine Piperazine (0,5 mol), 2-chloro-3-cyanopyridine (0,1 mol) and absolute ethanol (225 r
The mixture of n1) was heated under reflux for 16 hours. The cooled mixture was filtered to remove precipitated piperazine hydrochloride and the filtrate was evaporated under vacuum. The residue was diluted with water (200 m, 1 ml) and made basic (r+H>I) with 5N sodium hydroxide.
O) and extracted with ether (5X'300mf!)
I, ta.

The combined extracts were dried Le = (MgSO4) L and evaporated under vacuum to give 13.6 g of white solid (72.5% yield).
) was improved. m, p, -99-1(13)°C. The spectral data were consistent with the structure described in 1. This material was used below without further purification.

Step (b): Synthesis of N-[3-[3-(3-cyano-2-pyridinyl)-1-piperazinyl]propyl]-7talimide This reaction was carried out using the method of step (a) of Example 2 and the molar ratio. I went under. However, the product (0, (
13) 7 mol) was used instead of 1-(m-chlorophenyl)piperazine. The reaction yielded 14.1 g (yield ~100%) of an orange oil. The spectral data were consistent with the above structure. This material was used in a later step without further purification.

Step (C): 1-(3-amino-1-propyl)-4-
Preparation of (3~sia)-2-pyridinyl) piperazine This reaction was carried out under the method and moleization described in Example 1 step (b). Note that the product formed in step (b) of this example was used in place of the product of step (a) of Example 1. The reaction gave 7.6 g (83.5% yield) of an orange oil. The spectral data were consistent with the above structure. This material was used below without further purification.

Step (d): 6-chloro-2-[3-[4-(3-
cyano-2-pyridinyl)-1-piperazinyl]propyl]'-2,3-dihydro-1,3-
Synthesis of dioxo-1H-isoindole-5-sulfonamide This reaction was carried out in the manner and molar ratios described in step (C) of Example 1. Incidentally, the product of step (C) of this example (0,021
mol) was used in place of the product of Example 1 step (b). This reaction yielded 8.9 g of dark yellow solid bamboo. m, p, =] 90-200°C. When this material was crushed with hot methanol, 7.2 g (yield 7.
1%) of a yellow solid. m, p.

-200-2(14)°C (decomposed).

Elemental analysis 2C2゜1 (21C, i! N60. Theoretical value as S: C51,59; H4,33; N17.19 Actual value: C51,,76, H,4,36; N1.7.25
Spectral data showed that it had a monolithic structure.

Step (e): Preparation of the title product This reaction was carried out in the manner and under moleization described in step (d) of Example 1. However, the product of step (d) of this example (
0,012 mol) was used in place of the product of step (C) of Example 1. The reaction gave 5.3 g of a beige solid. This material was dissolved in 50 m, g of hot methanol and treated with 9N ethanolic hydrogen chloride (4 mfl),
The resulting solid was collected by filtration. This material was dried under vacuum (<0.05 mm Hg) at 80° C. for 16 hours to yield 3.07 g (49% yield) of 6-chloro-2-6.
Buddha 1″-1 [3~ [4-(3~cyano-2-pyridinyl)-E-
Piperazinyl]propyl]-2,3-dihydro-3-oxo-L H-isoindole-5-sulfonamide hydrochloride 0.75 H20 f4. m, p, -25
2-255°C (decomposed); white solid.

Elemental analysis: C21H33C, & N6(13)S −
Theoretical value as HCA 0.75820: [3g, 05;t(4,90;N16.0L
H202,57 Actual value: [37,79; H4,82; N15.81H2
02,73 Spectral data were consistent with the structure described above.

Example 7 1-, ['3-[5-(aminosulfonyl)
-6-chloro-1,3-dihydro-3-oxo-2H-isoindol-2-yl]-propyl]-4-benzoylpiperazine 1j This compound was converted into a hydrochloride-hydrate by the following steps. Prepared.

Step (a): N-[3-[3-(benzoyl)-1=
Synthesis of Piperazinyl]propyl]-phthalimide This reaction was carried out in the manner and molar ratios described in Example 2, step (a). However, 1-benzoylpiperazine (0,
023 mol) was used. This reaction yielded 8.4 g of a yellow solid (98% yield). m, p, -100-1 (
14)℃. Spectral data showed it to have the above structure.

Step (b): 1-(3-amino-1-propyl)-4-
The synthesis reaction of benzoylpiperazine was carried out using the method and molar ratio described in step (b) of Example 1, but the product of step (a) of this example (0,022
mol) was used instead of the product of step (a) of Example 1. This reaction produced 525 g of an orange oil (yield: 96.
5%) were photographed. The spectral data were consistent with the structure described in 1. This material was used below without further purification.

Step (C): ]-[3-[5-aminoalphonyl)-
6-chloro-1,3-dihydro-1,3-dioxo-2
Preparation of H-isoindol-2-yl]propyl]-4-benzoylpiperazine This reaction was carried out under the method and molar ratios in step (c) of Example 1, but not in step (b) of Example 1. In place of the product, the product of step (b) of this example (0,021 mol)
was used. This reaction gave a dark yellow solid.

This material was collected and triturated with methanol ether (1:1) to yield 4.1 g of a yellow solid (4% yield). m, p, -160-170t (decomposition).

The spectral data were consistent with the above structure. This material was used below without further purification.

Step (d): Preparation of the title compound This reaction was carried out according to the method and molar ratios of step (d) of Example 1. However, the product of step (C) of this example (0,
008 mol) was used in place of the product of Example 1 step (C). The reaction gave 3.1 g of foamy residue. Add this substance to 30mj of methanol! and treated with 9N ethanolic hydrogen chloride (5 mjl'), and the precipitate was collected. This material was incubated at 110°C for 16 hours under vacuum (<0.0
When dried under 5 mm mm 1 liter, 1.85 g (45% yield) of 1-[3-[5-(aminosulfonyl)
-6-chloro-1,3-dihydro-3-oxo-2H-
Isoindol-2-yl]propyl]-4-benzoylpiperazine hydrochloride hydrate was obtained. m, p, -1
78-220°C (decomposed).

White solid.

Elemental analysis: C22H25C#N, O2S・H [ll-H
2O Toshi'T: Theoretical value: [49,72; H5,
31; N 10.54; H2O3,39 Actual value: [39
,88;H5,24;N 10.48;H2O4,61
The spectral data were consistent with the above structure.

Example 8 1-[3-[5-(aminosulfonyl)10-chloro1,3-dihydro-3-oxo-2H-isoindol-2-yl]propyl]-1(4-fluorobenzoyl)-piperazine The compound was prepared according to the following steps.

Step (a): Synthesis of 4-fluorobenzoyl chloride A mixture of 4-fluorobenzoic acid (0.15 mol), thionyl chloride (0.45 mol), dimethylpolamide (5 drops) and chloroform (200 m, f. Heated at reflux for 16 hours. The volatiles were removed from the cooled solution under vacuum. The residue was diluted with carbon tetrachloride (100 mA) and the mixture was evaporated under vacuum to remove residual thionyl chloride.

The residue was distilled to give 19.7 g of a clear oil (yield 8
3%). At 40mmHg, p = 110
-112°C0 spectral data were consistent with the above structure.

Step (b): Synthesis of l-(4-fluorobenzoyl)piperazine A solution of piperazine (0,124 mol) in water (N10 mA) was heated with concentrated hydrochloric acid to adjust F+H to 2.8.

This solution was then heated to 50°C. 4-fluorobenzoyl chloride (0.124 mol) was added dropwise to the warmed solution while a 40% acetic acid aqueous solution was simultaneously added to maintain the pH at 2.8.

After the addition is complete, add potassium carbonate (47 g) to water (50 ml).
The solution was added and the mixture was cooled in a water bath.

This cold mixture was extracted with chloroform (5X150ml
)did. The combined extracts were dried (MgSO4) and evaporated under vacuum to give 22.5 g (88% yield) of a white solid. The spectral data were consistent with the above structure. This material was used below without further purification.

Step (C): Synthesis of N-C3-[4-(4-fluorobenzoyl-1-(piperazinyl)propyl]-phthalimide) This reaction was carried out using the method and molar ratio of step (a) of Example 1. , the product of step (b) of this example (0.05 mol) was used in place of 1-(o-methoxyphenyl)piperazine. The reaction yielded 22.6 g (yield ~1
00%) to give a yellow oil. The spectral data were consistent with the above structure. This material was used below without further purification.

Step (d)+1-(3-amino-1-propyl)-4-
The synthesis reaction of (4-fluorobenzoyl)piperazine was carried out according to the method and molar ratios of step (b) of Example 1, except that instead of the product of step (a) of Example 1, the product of step (C) of this example was used. The product ('0.(14) 9 mol) was used.

This reaction yielded 0.5 g (81% yield) of an orange oil. The spectral data were consistent with the above structure. This material was used without further purification.

Step (e) + 1- [3-[5-(aminosulfonyl)-6-chloro-1,3-dihydro-1゜3-dioxo-2H-isoindol-2-yl]propyl] -4
Preparation of -(4-fluoropenzoylpiverazine) This reaction was carried out under the method and molar ratios of step (C) of Example 1, except that the product of step (C) of this example (0,021 mol) was was used in place of the product of Example 1, step (b). The reaction yielded 9.5 g of a light brown solid. This material was crushed with methanol to give 7.0 g (65% yield).
) was obtained as a yellow solid. m, p, -185-188°C (decomposed). The spectral data were consistent with the above structure. This material was used without further purification.

Step (f): Preparation of the title compound This reaction was carried out in the manner and molar ratios of step (d) of Example 1. However, the product of step (e) of this example (0,012
mol) was used in place of the product of Example I step (C). This reaction yielded 6.0 g of foamy residue. This material was crushed by refluxing with 50 mj methanol (50 mj). The cooled mixture was filtered and the precipitate was incubated at 80°C for 72 h under vacuum (
< 0.05 mm) When dried under Ig), 3.7 g
(63% yield) of 1-[3-C3-(aminosulfonyl)-6-chloro-1,3-dihydro-3-oxo-2
H-isoindol-2-yl]propyl]-4-(4
~Fluorobenzoylpiperazine was obtained. m, p,
-113-124°C (decomposed); white solid.

Elemental analysis: C22L, Cn FN, O, S Theoretical value: C53,38; H4,89; It 11.32 Actual value: C53,27, H4,97; N 11.2B The spectral data is consistent with the title structure. was.

Example 9 6-chloro-2,3-dihydro-3-oxo-
2-[3-[3-(3-,()lifluoromethyl)phenyl]-1-piperazinyl]propyl)-18-isoindole-5-sulfonamide This compound was prepared as the hydrochloride salt 'A' according to the following steps. f1
It was prepared as 20.

Step (a): Synthesis of N-C3-[3-[3-()lifluoromethyl)phenyl]-1-piperazinyl]propyl]phthalimide This reaction was carried out according to the method of step (a) of Example 1 and the molar ratio. It was carried out below. Dari, 1-[3-()lifluoromethyl)phenyl]-piperazine (0,(14) mol)
was used in place of 1-(o-methoxyphenyl)piperazine in Example 1. This reaction yielded 15.8 g (yield 83%) of an orange oil. The spectral data were consistent with that of the above structure containing chloroform impurities. This material was used without further purification.

Step (b): 1(3-amino-1-propyl)-4-[
Synthesis of 3-()Lifluoromethyl)-phenylcopiperazine This reaction was carried out under the method and molar ratios of step (b) of Example 1. However, the product (0,
(13) (3 mol) was used in place of the product of step (a) of Example 1. The reaction gave 7.9 g (83% yield) of a clear oil. Spectral data were consistent with the above structure. This material was used below without further purification.

Step (C): 6-chloro-2,3-dihydro-1,
Synthesis of 3-dioxo-2-[3-[3-C3- (trifluoromethyl)phenyl]-1-piperazinyl]-propyl] 1H-isoindole-5-sulfonamide This reaction was carried out in step (a) of Example 1. ), but the product of step (b) of this example (0,0
21 mol) was used in place of the product of Example 1 step (b). This reaction resulted in 6.6 g of light brown solid (yield: 59
%) was obtained. m, p, -185-190°C. The spectral data were consistent with the above structure. This material was used below without further purification.

When this sample is crushed with heat (7 tones), m, p,
A pale yellow material of -190-1(22)°C (decomposed) was obtained.

Elemental analysis: C2°L2Cj! P3N-(14)3・0
．． 41 (as 20 CIt NH 20 theoretical value: 49.10 4.27 10.41
1.34 Actual value ko48.77 4.19 1(
1,580,97 Step (d): Structure of the title compound This reaction was carried out under the method and molar ratios described in step (d) of Example 1. However, the product of step (C) of this example (
0.011 mol) was used in place of the product of step (C) of Example 2. This reaction yielded 4.2 g of an orange solid. Dissolve this material in hot methanol (35ml) and
Crystallization was effected by treatment with 9N ethanolic hydrogen chloride (3 mj?). The resulting precipitate was collected and dried under vacuum (<0.05+nmHg) at 110°C for 16 hours to yield 2.4 g.
(Yield 4o%) (7) 6-chloro-2,3-dihydro-
3~oxo-2-[3~[4-[3~()! I-fluoromethyl)phenyl]-1-piperazinyl]-propyl:
]-]LH-isoindonyl-5-sulfonamide hydrochloride dihydrate was obtained. m, p, -220-222°C (decomposition).

White solid. Elemental analysis: C22L4Cjl' PGN-
(13) As 3'LC11・'AH20, 81 CHN H20 Theoretical value: 46.98 4.66 9.96 1
．． 60 Actual value: 47.144. t49.91 1.6
0 spectral data agreed with the above structure.

Example 10: 6-chloro-2,3-dihydro-3-oxo-2-[3-(4-phenyl-1-piperazinyl)propyl]-1H-isoindole-5-sulfonamide This compound is It was prepared as the hydrated hydrochloride salt according to the following process.

Step (a): Synthesis of N-[3-[4-phenyl-1-piperazinyl)propyl)phthalimide This reaction was carried out in the manner and molar ratios described in step (a) of Example 1, except that Example 1 0.019 mol of N-phenylpiperazine was used instead of 1-(0-methoxyphenyl)piperazine. Due to this reaction, 6. (13) g (yield 9
3%) of a yellow solid was obtained. m, p, = 105-122℃
. The spectral data were consistent with the above structure.

Step (b): 1-(3-amino-1-propyl)-4-
Synthesis of phenylpiperazine This reaction was carried out under the method and molar ratios of Example 1 step (b), except that the product of Example 1 step (a) (0,017 mol) was was used in place of the product.

This reaction yielded 3.44 g (93% yield) of a yellow oil. The spectral data were consistent with the above structure. This material was used below without further purification.

Step (C): 6-chloro-2,3-dihydro-1,
Synthesis of 3-dioxo-2-[3-(4-7enyl-1-piperazinyl)propyl]-1H isoindole-5-sulfonamide This reaction was carried out according to the method of step (C) of Example 1 and under moleization. The product of step (b) of this example (0.015 mol) was used in place of the product of step (b) of Example 1. The reaction yielded 5.2 g (75% yield) of m,p.

It gave a yellow solid with a temperature of -90-130°C (decomposition).

0.55 g of this material was crushed with acetonyl II to give 0.42 g of a yellow solid with m, p, -173 to 178°C (decomposed).

Elemental analysis: C2, H2, CflN4(14)S・0.
CII N) 1 20 as 331120 Theoretical value: 53.79 5.09 11.95
1.28 Actual value: 54.07 5.07 1
2.22 1.44 Spectral data agreed with the above structure.

Step ω): Preparation of the title compound This reaction was carried out under the method and molar ratio of step (d) of Example 1. However, the product of step (C) of this example (0.01 mol) was used instead of the product of step (C) of Example 1. This reaction gave 2.2g of yellow solid.

This material was dissolved in methanol (25 ml) and crystallized by treatment with 9N ethanolic hydrogen chloride solution (3 ml). The generated precipitate was collected and heated at 110°C for 16 hours.
When dried under vacuum (<0.05 mmHg), 0.95 g (19.5% yield) of 6-chloro-2,3
~dihydro-3~oxo-2-[3~(4-7enyl-1-piperazinyl)propyl]-1H-isoindole-5~sulfonamide (m, p, -210-225°C,
Decomposition) was obtained as a white solid.

Elemental analysis: C2, +125 [[N, (13) S・HCA
・1' as 0.67H20: HN H20 theoretical value: 50
．． 72 5.54 11.27 2.39 Actual value: 50.89 5.45 11.18 2.28
The spectral data were consistent with the above structure.

Example 11: 6-chloro-2,3-dihydro-2-[3
Preparation of -[4-(2-methoxyf, 85 phenyl)-1-piperazinyl]butyl]-3-oxo-1H-isoindole-5-sulfonamide This compound was prepared as follows.

Step (a): Synthesis of N-[4-[3-(2-methoxyphenyl)-1-piperazinyl]-phthalimide This reaction was carried out using the method and molar ratio of Example 1 step (a). However, N-(4-bromobutyl)phthalimide was used instead of N-(3-bromopropyl)-phthalimide, and 1-(o-methoxyphenyl)piperazine was
．． (13) 5 mol was used.

The reaction gave 14.2 g (~100% yield) of a yellow oil. The spectral data were consistent with the above structure containing a chloroform indurate. This material was used below without further purification.

Step (b) co-1-(4-amino-1-butyl)-4-(
The synthesis reaction of 2-methoxyphenyl)piperazine was carried out using the method and molar ratio described in step (b) of Example 1.
mol) was used instead of the product of step (a) of Example 1. The reaction gave 10.7 g (~100% yield) of a pale yellow oil. The spectral data were consistent with the above structure. This material was used below without further purification.

Step (C): 6-chloro-2,3-dihydro-1,
The synthesis reaction of 3-thioxo-2-[3-[3-(2-methoxyphenyl)-1-piperazinyl]butyl]-1H-isoindole-5-sulfonamide was carried out by the method of step (C) of Example 1 and Performed under molar ratio. However, the product of step (b) of this example (0,02'
1 mol) was used in place of the product of Example 1 step (b). This reaction gave 6.1 g of a yellow solid. Crush this substance with acetonyl (25 mj), m, p,
Light yellow solid with = 205-250°C (decomposition) 4.7
g (yield 44%) was obtained. Spectral data and elemental analysis were consistent with the above structure.

Step (d): Preparation of the title compound The reaction was carried out according to the method and molar ratio of step (d) of Example 1. However, the product of step (C) of this example (0,009
mol) was used in place of the product of Example I step (C).

The reaction gave 2.94 g of a beige solid. After crushing this substance with methanol (10n+4 liters), 2.
m, p at 10 g (yield 48.8%).

6-chloro-2,3-dihydro-2-[3-[
3-(2-Methoxyphenyl)-1-piperazinyl]butyl]-3-oxo-1H-isoindole-5-sulfonamide was given as 1st.

Elemental analysis: C23H2,C, &N, 0. C as S
HN theoretical value: 56. (13) 5.95 11.36
Actual measurements: 56.13 6.06 11.23 The spectral data were consistent with the structure described in 1.

Example 12 6-chloro-2,3-dihydro-2-[l-
(3-fluoro-6-methoxyphenyl)-1-piperazinyl]propyl]-3-fluoro-1H-isoindole-5-sulfonamide This compound was prepared as follows.

Step (a): Synthesis of 1-fluoro-3-nitro-4-methoxybenzene Fuming nitric acid (90%, 0.36 mol), ■-fluoro-4-methoxybenzene (0.3 mol), 3 and vinegar H (1
mol) and acetic anhydride (0.4 mol) at 0°C. The reaction mixture was warmed to room temperature and poured into ice water after 1 hour, thus giving 31 g (I15f261
%) to obtain 1-fluoro-3-nitro-4-methoxybenzene.

Step (b): Synthesis of 5-fluoro-2-methoxyaniline 40
1-Fluoro-3-ditro-4-methoxybenzene (34 g) was reduced in 0++42 ethanol. The mixture was filtered and concentrated and used without further purification.

Step (C) + Synthesis of 1-(3-fluoro-6-methoxyphenyl)piperazine 5-fluoro-2-methoxyaniline (0,0(22)
mol), bis(2-chloroethyl)-amine hydrochloride (0
The mixture was stirred and refluxed for 20 hours. Water was added to the reaction solution,
The organic layer was discarded. The aqueous layer was made basic with sodium hydroxide and extracted with methylene chloride (2xlOOme). The methylene chloride extract was dried over carbonic acid, filtered, and concentrated. The residue was distilled to 0.15 mmHg.
8.8 g (45% yield) of piperazine product of 11 ml H° C. was obtained.

Step (d): N-[3-[4- (3-fluoro-6-
methoxyphenyl)-1-piperazinyl]propyl]-
The synthesis reaction of phthalimide was carried out using the method and molar ratio of step (a) of Example 1. However, 1-(3-fluoro-6-methoxyphenyl)piperazine (0,(14) 2 mol) was used instead of -(O-methoxyphenyl)piperazine. This reaction gave 16.7 g (100% yield) of phthalimide intermediate.

Step (e):1. -(3-amino-1-propyl)-4
Synthesis of -(3-fluoro-6-methoxyphenyl)piperazine The reaction was carried out according to the method and molar ratio of step (b) of Example 1. However, the product of step (d) of this example (0,012 mol) was used in place of the product of step (a) of Example 1.

This reaction gave 27 g (82% yield) of the amino intermediate. This was used below without further purification.

Step (f): 6-ri-4-row 2.3-dihydro-2-
Synthesis of [3-[4-(3-fluoro-6-methoxyphenyl)-1-piperazinyl]furovir]-1,3-dioxo-1H-isoindole-5-sulfonamide Step (C) of Example 1 The reactions were carried out according to the method and molar ratio. However, instead of the product of step (b) of Example 1, the product of step (e) of this example (0, (14) 2 mol) was used. This reaction gave 16.7 g (100%) of the 1,3-dioxo intermediate, which was used below without purification.

Step (marked: Preparation of the title compound) The reaction was carried out in the manner of step (d) of Example 1 and under moleization, except that instead of the product of step (C) of Example 1, step (f) of this example was used. ) was used (0.0'15 mol). The crude product was dissolved in methanol to make the hydrochloride salt. The hydrochloride salt was dissolved in methanol and saturated bicarbonate was added) I
Treatment with Jum solution gave the free base. The mixture was refluxed for 5 minutes and water was added. The resulting solid was collected, dissolved in methylene chloride, dried over MgO, filtered, and concentrated to give m, p, 6-chloro-2,3 at -158-163 °C.
~dihydro-2-[3~ (4-(3~fluoro-6-
methoxyphenyl)-1-piperazinyl]propyl]-
1.6 g of 3-oxo-1H-isoindole-5-sulfonamide was obtained.

Elemental analysis: C22H26CA FN, 0. C as S
II N Theoretical value + 53.17 5.27 11.27 Actual value: 53.52 5.52 11.38 Example 1
36-chloro-2,3-dihydro-2-[3-[4-(
4-Fluoro-2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide This compound was prepared according to the following steps.

Step (a) + Synthesis of 5-fluoro-2-methoxyaniline 1-fluoro-3-methoxy-4-nitrobenzene (0 , 11 mol) was reduced according to step (b) of Example 12. Thus 14.
8 g (98% yield) of 5-fluoro-2-methoxyaniline was obtained, which was used below without purification.

Step (b): Synthesis of 1-(4-fluoro-2-methoxyphenyl)piperazine Bis(2-chloroethyl)-amine hydrochloride (0.11 mol) and 5-fluoro-2-methoxyaniline (0.01
mol) was carried out according to step (C) of Example 12 to obtain 19.5 g (95% yield) of the piperazine derivative. This was used below without purification.

Step (C): The synthesis reaction of N-[3-[3-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]propyl]phthalimide was performed according to the method and molar ratio of step (8) of Example 1. However, 1-(4-fluoro-2-methoxyphenyl)piperazine (0.05 mol) was used instead of 1-(o-methoxyphenyl)piperazine. This reaction is 18.
Yielded 1 g (96%) of an orange-brown oil. This was used below without purification.

Step (d): 1-(3-amino-1-propyl)-4=
Synthesis of (4-fluoro-2-methoxyphenyl)piperazine The reaction was carried out using the method and molar ratio in step (b) of Example 1. However, instead of the product of step (a) of Example 1, the product of step (C) of this example was used. The reaction yielded 1 tsubo of an amber-orange oil, 10.4 g (86%), which was used below without purification.

Step (e): 6-chloro-2,3-dihydro-2-
C3~[3-(4-fluoro-2-methoxyphenyl)
-1-piperazinyl]furovir]-1,3-dioxo-
Synthesis of IH-isoindole-5-sulfonamide The reaction was carried out using the method and molar ratio of step (C) of Example 1. However, the product of step (d) of this example was used instead of the product of step (b) of Example 1. The product of this reaction is n
- stirred with hebutane and filtered to give 16°7 g (45%
A 1,3-dioxoisoindole intermediate with m, p, = 100-115°C was obtained.

This was used below without purification.

Step (f): Preparation of the title compound The reaction was carried out under the method and molar ratio of step (d) of Example 1, but instead of the product of step (C) of Example 1, this example step ( The product of e) (0,(13) mol) was used.

The crude product was crystallized from ethyl acetate to yield 6.14 g (
6-chloro-2,3-dihydro-2-[3[L-(
4-Fluoro-2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide was obtained.

Elemental analysis: 62°H26 [l1FN, (14) as S) C) I N Theoretical value: 53.17 5.27 11.27 Actual value: 53.24 5.42 11.60 Example 1
4 The diuretic effects of the compounds synthesized in Examples 1 to 11 were tested. The compound of Example 1 is its monohydrochloride 2-propalate hydrate, namely [, 2112. CAN, 0. S・IC, Il!・0.
2 (CH3) 2C1-1011・0.151120
Tested as '97. This test was performed using the diuretic screening method previously described and by Fuschitz et al. In Table 1 below, "volume ratio" indicates the ratio of the total excreted volume of the test compound to the total excreted volume of the control, and "Na+ ratio" indicates the ratio of the total excreted volume of the test compound to the total excreted volume of the control.
The "K+ ratio" is the ratio of Na+ excreted by the test compound to that excreted by the control. Test No. ], 2.6.7.11
-29 is a female Sprague dowlei.
Daw Iey> rats were used. Testing male Aoki Okamoto (Dkamata-^oki) rats
o, 3-5 and 8-10. Antihypertensive activity tests were conducted simultaneously on test No. 3 to 5 rats. In some cases, the same dose level was retested.

The results are as follows.

This test showed that all compounds of Examples 1-11 had diuretic (total urine volume) and/or natriuretic activity.

Example 15 The compounds of Examples 1 to 12 were tested for antihypertensive activity. All compounds were tested in spontaneously hypertensive rats as described above. In the case of the compounds of Examples 1-4, they were also tested in rats hypertensive with DOCA-salts. The compound of Example 1 is
Its monohydrochloride 2-propalate hydrate, i.e. C22H
□7c A N40. S・HC, &・0.2 ([l+
3) Used in tests 1-5 as 2C1lrltl・0.15HJ. Also 3/4 molar hydrochloride, i.e. C22
112, c A N, (14) S ・3/4 Test 3a as HCA.

4a, 5a-56. The test results are shown in Table 2 below, where SHR stands for spontaneously hypertensive rats, DOCA stands for DOCA-salt-induced hypertensive rats, and 8BP is the cardiac H systolic in mm It g. ΔHR represents the change in average heart rate expressed in beats per minute, and the time shown represents the elapsed time after administration.

A peak change of 20 or more in 8 BP is considered to be indicative of activity.

Table 2 1 [)2 Δ RT) Δ Hp Δ T:l
T) Δ Hp-jl 4 mm11g
) This test was performed using Examples 1.2.3.4.5.9.10.
Compounds 11 and 12 have been shown to have good antihypertensive effects without significantly affecting heart rate.

Example 16 In this example, Example 1 (improved), 2.3.5.6.7.8
．． 9. Deitchman et al.'s Journal of Pharmacological Methods for compounds 10 and 11.
acological method), 1980
．． In vivo α-shielding activity was tested in rats according to the methodology described on page 312 of 3.311-321. In this test, phenylephrine (hereinafter referred to as PE) or norepinephrine (hereinafter referred to as NE) was administered as an α-agonist to rats before and after administration of the test reagent. The mean extrapolated dose or PE/NE was observed to be effective in producing a 50 mmHg increase in mean arterial blood pressure.

The results are shown in Table 3. In this table, ED5o represents the above average extrapolated dose and "average dose shift" represents the average ratio of ED5° after drug administration to ED5o before drug administration. 2-propart hydrate, namely C22H2□C, &N4n4S -116# ・0.
2 (CH3) 2CHI1H・0.1511J) used in Tests 1-5, and 3 in Tests 2a and 3a.
/4 mol hydrochloride, i.e. [l:,l+27CA N,O,
It was used as S.3/4HC, g. The route of administration is intravenous (i, v,), but test 2a13.3a.

In 26-29, the route was oral.

Prazosin (0, (13) mg/kg; i, v,)
produced a dose shift of approximately 30 in response to PE and showed a shift of 5-10 to NE.

Table 3 The above results show that the compounds of Examples 1.2.3.6.10 and 11 are active as α-shielders in vivo, with the compound of Example 9 being slightly active.

Example 16 In this example, instead of 1 mole of HCβ, 3l4 moles of UCl
the hydrochloride salt of the compound of Example 1 containing C2□11□,
CA N, O, S・3/411 [11' (hereinafter referred to as MJ1
5(13)7-IA) with respect to diuretic properties,
Compare with prazosin, an antihypertensive agent with shielding activity.

This study involved 150-200 g non-anesthetized Sprague-Dawley rats [Charles River Laboratories, Wilmington,
Wilmington, MA], and the protocol of Hanson et al.
t1Metab, ), 1982.8.314-324
] was used.

Animals were maintained in a temperature-controlled room in stainless steel group cages, with a 12-hour light, 12-hour extinction cycle, and housed in Bryna Rhodes love chews (Pur
ina Rodent Lab Chow) and water was provided ad libitum. All animals were fasted for 18 hours before the first dose and were not given water during the experiment.

In this experiment, the dose of MJ15(13)7-IA was 3.0
mg/kg, and the dose of prazosin is 0.3 mg
/kg. Groups of 10 animals (2 animals per cage)
I looked into it. A control group (non-medicated) of the same number of animals is included.

The test drug was 0.25% methocel-physiological saline (0.9%
The suspension was suspended in NaC, and the above dose was orally administered via back tube method.

The oral fluid administration volume containing each drug dose was 25 m,j/
It was kept at kg. Controls received methocel-saline vehicle only. Urine was collected at 5 hour intervals from rats housed in metabolic cages (2 rats per cage). One specimen consists of freshly pooled samples from each cage. Volume of urine excreted by multiple rats (ml)
and electrolyte concentration (Na, K, C1l, C
a5P concentration) using an AAIT automatic analyzer [Technicon (T
echnicon)] using an established method. At the end of the acute phase (1 day), multiple pairs of rats were returned to separate cages (2 per cage) and given food and water.

For the next 3 days, each animal received each drug methocel-saline loading solution by back gavage. On day 5 (after 18 hours of fasting), all rats were handled again and placed in metabolic cages for urine collection every 5 hours (chronic administration: 5 days).

MJ15(13)7-IA (3,0 mg/kg orally) did not show any natriuretic/diuretic effects after acute treatment (1 day), but after long-term administration (5 days).
Increased IJum excretion and increased chloride excretion were observed (32 and 31% increase over control, respectively). Prazosin showed antidiuretic properties (Na'J than control).
3 and showed a significant decrease in CIl excretion: 0.3 from the mouth.
mg/kg).

Example 18 In this example, for the compounds of Examples 1 to 11, α and C
2 binding was tested in vitro. The compound of Example 1 is monohydrochloride 2-propanoate hydrate, i.e. C22H2
7CβN, 0.3・IC!・0.2 (C1,)2CI
Tested as IDH・0.15820.

In this test, specific brain tissue was prepared as a source of binding sites. Washed tissue aliquots were incubated under low concentrations of test compound. After incubation at the appropriate temperature, the reaction mixture was processed to separate the membrane-bound radioligand. When the radioactivity was measured and the linear regression analysis of the probit value for the proportion of binding caused by the presence of the compound of interest at various concentrations was plotted against the compound concentration, it was found that 50
% specific binding inhibition concentration ■C5o was obtained. In this test, the buffer was 50mM Hepes, pH 7.4.
It is K leaf. The ligand was C'H3WB-4' 101 for α, manufactured by New England Nurirea Co., Ltd. (N
[3H]clonidine was used as a ligand for α2 from New England Nuclear in a unidirectional manner.

The results were compared and discussed with 7-entolemine methanesulfonate as a standard substance. This is known as an excellent α-conjugate. The results are shown in Table 4 below.

Table 4 The results of Table 4 are as follows: Examples 1.2.3.4.10 and 1
The compound of Example 1.1 has C1-binding activity and Example 1.2
．． Compounds 3 and 10 are shown to have C2-binding activity.

Example 19 Other compounds were prepared as follows, substituting the appropriate piperazine for 1-(0-methoxyphenyl)piperazine in Example 1.

These compounds are compounds in which X is Cβ in general formula (1).

Example No. Y R1R2R318
-1-substituted phenyl CN1l■18-2
Substituted phenylalkyl CH, HR18-3〃0CII
3HH 1B-4〃CF, HR 18-5'/'0CH2H5,1+"
HlB-61111 phenylcarbonyl Cj! )lHl
B-7'0CH3HH 1B-8〃C3H7HH 18-! ]〃CF, HR18-1
0-substituted 2-pyridinyl m HH These compounds have use as diuretic and/or IJ excretion enhancers.

Example 20 Compound similar to Examples 1 to 13, i.e., X of general formula (1)
is CF3 instead of CIl, as 4-chloro-
Instead of 5-sulfamoylphthalimide, an equimolar amount of 4
~Prepared using trifluoromethyl-5-sulfamoylphthalimide.

For example, 2.3-dihydro-2-[3-[4-(2-methoxyphenyl)-1-piperazinyl]-propyl]-
3-Oxo-6-trifluoromethyl-1H-isoindole-5-sulfonamide is obtained by performing the above substitution in Example 1.

These compounds have use as diuretics and/or natriuretics.

Example 21 6-chloro-2,3-dihydro-2-[3-
Synthesis of [3-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide The target compound of Example 1 can also be synthesized as follows.

Step (a): Synthesis of /]-chloro-2-methylbenzoic acid methyl ester (2) 4-chloro-2-methylaniline is diazotized, and the diazonium salt is rearranged with cupric cyanide to the 2) IJ-yl form. , 4- obtained by hydrolyzing itself with acid
Chloro-2-methylbenzoic acid ('') (85 g; 0.5 mol) solution, 1 m, g of dimethylformamide and 2
50 mjl' of thionyl chloride was refluxed for 2 hours. The solvent was removed under reduced pressure and the resulting residue was poured into 250 mj2 of methanol and stirred overnight. Methanol was removed under reduced pressure to obtain 83.2 g (yield 90%) of a pale yellow liquid.
is the first prize.

Step (b): Synthesis of methyl 4-chloro-5-chlorosulfonyl-2-methylbenzony) (3) 15.8 g (0,086 mol) of methyl 4-chloro-
2-methylbenzoff--) (2) and 25.8m, C(
A mixture of 45.2 g (0.39 mol) of chlorosulfonic acid was heated to gentle reflux under a nitrogen atmosphere.

After 3 hours, the mixture was cooled and poured slowly into an ice-water mixture. After stirring for 1 hour, the mixture was filtered and washed thoroughly with ice-cold water. Dry in a vacuum oven (60℃),
7.4 g (0,065 mol; yield 75%) of the sulfonylated acid (off-white crystals) was obtained. 14.5 g of acid, 2 drops of dimethylformamide, and 50 mA of thionyl chloride were heated to reflux under a nitrogen atmosphere. After 1.2 hours, the solvent was removed under reduced pressure, methanol (125 mj) was added to the residual material, and the solution was cooled to 10°C. After 5 hours,
The solids were filtered and air dried. m, p, -94,5-96
12.5 g of off-white crystals were obtained.

Step (C) Synthesis of dimethyl 5-aminosulfonyl-2-bromomethyl-2-chlorobenzoate (4) 12.0 g (0, (14) 2 mol) of compound (3)
, 15.1 g (0,085 mol) N-bromosuccinimide (NBS), 0.5 g 2,2'-azo-bis-
A mixture of (2-methylpropionitrile) and 75 mA of carbon tetrachloride was heated to reflux under a nitrogen atmosphere. Every 2 hours, the reaction mixture was examined by NMR to determine the ratio of starting material to desired product.

The highest starting material to desired product ratio obtained was 35:65.
Met. If this mixture is further reacted, the products are decomposed. After checking the reaction by NMR, an additional 0.3 g
2.2'-azo-bis-(2-methylpropionitrile) was added. After the desired ratio is achieved, the mixture is cooled to room temperature.

The mixture was filtered and the filtrate was concentrated under vacuum to give an oil. This was used in the following steps without purification. This oil was dissolved in 200 mC of a 3:1 methanol:tetrahydrofuran mixture. After cooling to 0°C,
A solution of 5.0 mβ concentrated ammonium hydroxide solution in 50 mA water was added. After 5 minutes, dilute the solution with 30mj of 10% hydrochloric acid solution! Acidified by addition of 25 On+j! and part of the organic phase removed under vacuum, then 25 On+j! of water was added. The solid was filtered off and dried to obtain 4.0 g (0,012 mol; yield 28%) of a white powder. This was a mixture of the desired intermediate (4) and unbrominated material as shown by NMR.

Step ω) Synthesis of the title compound], Purified compound (4) of Og (2.9 mmol),
fffl Potassium hydrcarbonate (3,6+nmol>, I
-(3-amino-1-propyl)-4-(2-methoxyphenyl)piperazine (3,6 mmol) and 17t
r#! The mixture of acetonyl and IJ was stirred at room temperature under nitrogen atmosphere. This stirring is completed until the reaction is completed and 6-chloro-2,3-dihydro-2-C3-[3-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-
This was continued until oxo-1H-isoindole-5-sulfonamide was obtained and then isolated and purified as described in Example 1.

Various other variations will be apparent to those skilled in the art.

Accordingly, the scope of the invention is defined by the claims that follow.

Claims (33)

[Claims] (1) General formula (I): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(I) However, in the general formula (I), X is a halogen atom or a trifluoromethyl group, and n is 2 to
It is an integer in the range of 5, and Y is (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, (c) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼or (d)
▲There are mathematical formulas, chemical formulas, tables, etc.▼, where R_1 is a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a cyano group, and R_2 is a hydrogen atom, a halogen atom, a lower A compound or a pharmaceutically acceptable salt thereof, which is an alkyl group or a lower alkoxy group, and R_3 represents a hydrogen atom or a cyano group. (2) In the above general formula (I), X is a halogen atom, n is an integer of 2 to 4, and Y is (a),
The compound or a salt thereof according to claim (1), wherein R_1 is a hydrogen atom or a halogen atom, and R_2 is a hydrogen atom, a lower alkyl group, or a lower alkoxy group. (3) The compound or a salt thereof according to claim (2), wherein X is a chlorine atom and R_1 is a hydrogen atom. (4) The compound or a salt thereof according to claim (3), wherein R_2 is a lower alkoxy group. (5) The compound or a salt thereof according to claim (4), wherein R_2 is a methoxy group. (6) The compound or a salt thereof according to claim (5), wherein n is 3. (7) 6-chloro-2,3-dihydro-2-[3-[4
The compound according to claim (1), which is -(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide. (8) Patent for 6-chloro-2-[3-[4-(3-chlorophenyl)-1-piperazinyl]propyl]-2,3-dihydro-3-oxo-1H-isoindole-5-sulfonamide A compound according to claim (1). (9) 6-chloro-2,3-dihydro-2-[2-[4
The compound according to claim (1), which is -(2-methoxyphenyl)-1-piperazinyl]ethyl]-3-oxo-1H-isoindole-5-sulfonamide. (10) 6-chloro-2,3-dihydro-2-[3-[
The compound according to claim (1), which is 4-(2-methylphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide. (11) 6-chloro-2,3-dihydro-3-oxo-
The compound according to claim (1), which is 2-[3-[4-(phenylmethyl)-1-piperazinyl]propyl]-1H-isoindole-5-sulfonamide. (12) 6-chloro-2-[3-[4-(3-cyano-
2-pyridinyl)-1-piperazinyl]propyl]-2
,3-dihydro-3-oxo-1H-isoindole-
The compound according to claim (1), which is a 5-sulfonamide. (13) 1-[3-[5-(aminosulfonyl)-6-
The compound according to claim (1), which is chloro-1,3-dihydro-3-oxo-2H-isoindol-2-yl]propyl]-4-benzoylpiperazine. (14) 1-[3-[5-(aminosulfonyl)-6-
Claim No. 1 which is chloro-1,3-dihydro-3-oxo-2H-isoindol-2-yl]propyl]-4-(4-fluorobenzoyl)-piperazine
) Compounds described in section 2. (15) 6-chloro-2,3-dihydro-3-oxo-
Claim No. 2-[3-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]propyl]-1H-isoindole-5-sulfonamide (
Compound described in section 1). (16) 6-chloro-2,3-dihydro-3-oxo-
The compound according to claim (1), which is 2-[3-[4-phenyl-1-piperazinyl]propyl]-1H-isoindole-5-sulfonamide. (17) 6-chloro-2,3-dihydro-2-[4-[
The compound according to claim (1), which is 4-(2-methoxyphenyl)-1-piperazinyl]butyl]-3-oxo-1H-isoindole-5-sulfonamide. (18) 6-chloro-2,3-dihydro-2-[3-[
Claim No. 4-(3-fluoro-6-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide (
Compound described in section 1). (19) 6-chloro-2,3-dihydro-2-[3-[
Claim No. 4-(4-fluoro-2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide (
Compound described in section 1). (20) Hypertension treatment comprising regularly administering to a mammal an antihypertensive effective amount of the compound according to claim (1) or a pharmaceutically acceptable salt thereof according to the necessity of the treatment. Method. (21) The compound is 6-chloro-2,3-dihydro-2-
Claim No. (20) which is [3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide
Treatment method described in section. (22) A pharmaceutical composition comprising a hypertension-suppressing amount of the compound according to claim (1) or a pharmaceutically acceptable acid addition salt thereof, and a pharmaceutically acceptable carrier. (23) The compound is 6-chloro-2,3-dihydro-2-
Claim No. (22) which is [3-[4-(2-methoxyphenyl)-1-piperazinyl]propyl]-3-oxo-1H-isoindole-5-sulfonamide
Pharmaceutical compositions as described in Section. (24) (a) Step of reducing the 1,3-dioxoisoindole compound of the following formula (VII) or the 1-hydroxy-3-oxoisoindole compound of the following formula (VIII): ▲Mathematical formula, chemical formula, There are tables, etc. ▼ (VII) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ However, X is hydrogen or trifluoromethyl, n is an integer from 2 to 5, and Y is (a) ▲ Numerical formulas, chemical formulas, tables, etc. There are ▼, (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, (c) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ or (b)
▲There are mathematical formulas, chemical formulas, tables, etc.▼ where R_1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a cyano group, and R_2 represents a hydrogen atom, a halogen atom, a lower Represents an alkyl group or lower alkoxy group, R
_3 represents a hydrogen atom or a cyano group, (b) 4-aminopiperidine compound of the following general formula (V): ▲ Numerical formula, chemical formula, table, etc. are available ▼ (V) where n and Y are as defined above is, a sulfamoyl compound of the following formula (IX) in an inert solvent: ▲Mathematical formula, chemical formula, table, etc.▼(IX) Here, X is as defined above, R_5 is an amino group,
a halogen atom or a lower alkoxy group, R_4 represents a carbamoyl or formyl group as a halogen atom or R_4CH_2- group, and R_5 and R_4 may represent an oxygen atom together; Formula (X): ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (X) However, n and X are as defined above.
) Here, Y is as above, and Z is a reactive leaving group. Step of reacting with a compound represented by ▼(I) A method for producing a compound, wherein X, n and Y are as defined above. (25) Furthermore, the compound of (a) (i) Formula (II) - ▲There are mathematical formulas, chemical formulas, tables, etc.▼(II) and the compound of formula (III): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(III ) in the presence of a base under reaction conditions to form a compound of formula (IV): ▲Mathematical formula, chemical formula, table, etc.▼(IV)
i) The above compound (IV) and hydrazine are brought into contact to form the formula (
V): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(V) Process of forming the compound of formula (V); (iii) Compound of the above formula (V) and formula (VI): ▲Mathical formula,
A method that includes the step of reacting a compound of formula (VII) with a chemical formula, table, etc.▼(VII) under reaction conditions that can form a compound of formula (VII): (b) then reducing said compound of formula (VII) under reaction conditions capable of forming a compound of formula (I); The method according to claim (24), characterized in that: (26) The reduction in step (b) above is performed under conditions such that a compound of formula (VIII): ▲Mathematical formula, chemical formula, table, etc.▼(VIII) is formed during the reduction of the compound of formula (VII) Process according to claim 25, characterized in that the compound of formula (VIII) is optionally separated. (27) General formula (VIII): ▲There are mathematical formulas, chemical formulas, tables, etc.▼(VIII) (However, X is hydrogen or trifluoromethyl,
n is an integer from 2 to 5, and Y is (a) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, (b) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼, (c) ▲ Mathematical formulas, chemical formulas, tables, etc. There is ▼ or (d)
▲There are mathematical formulas, chemical formulas, tables, etc.▼, where R_1 represents a hydrogen atom, a halogen atom, a lower alkyl group, a lower alkoxy group, a trifluoromethyl group, or a cyano group, and R_2 represents a hydrogen atom, a halogen atom, Represents a lower alkyl group or a lower alkoxy group, R
_3 represents a hydrogen atom or a cyano group. ) compounds. (28) The compound of formula (I) is administered at a daily dose of 3
21. The method according to claim 20, wherein the method is orally administered at a dose of ~300 mg. (29) The compound of formula (I) is administered at a daily dose of 7
29. The method according to claim 28, wherein the method is orally administered at a dose of ~280 mg. (30) 0.3 to 100 mg of the compound of formula (I)
Claim No. (
20) The method described in section 20). (31) The method according to claim (21), wherein the compound of formula (I) is administered at a dose of 3.0 to 30 mg/kg based on the body weight of the mammal. (32) The method of claim (22), wherein the composition is in dosage units suitable for single or multiple administration. (33) A method characterized by preparing a compound according to any one of claims (1) to (19).